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22 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2018/01/18PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Related Articles Impact of genistein on the gut microbiome of humanized mice and its role in breast tumor inhibition. PLoS One. 2017;12(12):e0189756 Authors: Paul B, Royston KJ, Li Y, Stoll ML, Skibola CF, Wilson LS, Barnes S, Morrow CD, Tollefsbol TO Abstract Since dietary polyphenols can have beneficial effects in prevention and treatment of cancer, we tested the hypothesis that breast cancer patients' intestinal microbiota is modulated by genistein (GE), an isoflavone found in soy, and that microbial alterations may offset the side effects brought about by chemotherapy. We demonstrated successful humanization of germ-free mice by transplanting fecal samples from breast cancer patients before and after chemotherapy. Mice were then grouped based on chemotherapy status and GE or control diet. We did not find any significant differences between pre-chemotherapy and post-chemotherapy bacterial composition and abundances. Germ-free mice on a GE diet showed differences in microbial composition as compared to mice on control diet. Four weeks after introduction of the customized GE diet, there was distinct clustering of GE-fed mice as compared to the control-fed group. In the gut microbiome of GE-treated humanized mice, there was an increase in abundance of genera Lactococcus and Eubacterium. Phylum Verrucomicrobia showed statistically significant (p = 0.02) differences in abundances between the GE-fed and control-fed groups. There was an increase in bacteria belonging to family Lachnospiraceae and Ruminococcaceae in GE-fed mice. Marked changes were observed in GE catabolism in mice humanized with fecal material from two of three patients' post-chemotherapy with complete disappearance of 4-ethylphenol and 2-(4-hydroxyphenol) propionic acid conjugates. The post-tumor samples did not show any distinct clustering of the gut microbiota between the two diet groups. There was an increase in latency of about 25% for tumor growth of the humanized mice that were on a GE diet as compared to humanized mice on a control diet. The average tumor size for the GE group was significantly decreased compared to the non-GE group. Collectively, our results suggest that the intestinal microbiota becomes altered with a GE diet before induction of tumor. Our findings indicate that GE modulates the microbiome in humanized mice that may contribute to its effects on increasing the latency of breast tumor and reducing tumor growth. PMID: 29267377 [PubMed - in process]

Related Articles Metabolomic profiling and stable isotope labelling of Trichomonas vaginalis and Tritrichomonas foetus reveal major differences in amino acid metabolism including the production of 2-hydroxyisocaproic acid, cystathionine and S-methylcysteine. PLoS One. 2017;12(12):e0189072 Authors: Westrop GD, Wang L, Blackburn GJ, Zhang T, Zheng L, Watson DG, Coombs GH Abstract Trichomonas vaginalis and Tritrichomonas foetus are pathogens that parasitise, respectively, human and bovine urogenital tracts causing disease. Using LC-MS, reference metabolomic profiles were obtained for both species and stable isotope labelling with D-[U-13C6] glucose was used to analyse central carbon metabolism. This facilitated a comparison of the metabolic pathways of T. vaginalis and T. foetus, extending earlier targeted biochemical studies. 43 metabolites, whose identities were confirmed by comparison of their retention times with authentic standards, occurred at more than 3-fold difference in peak intensity between T. vaginalis and T. foetus. 18 metabolites that were removed from or released into the medium during growth also showed more than 3-fold difference between the species. Major differences were observed in cysteine and methionine metabolism in which homocysteine, produced as a bi-product of trans-methylation, is catabolised by methionine γ-lyase in T. vaginalis but converted to cystathionine in T. foetus. Both species synthesise methylthioadenosine by an unusual mechanism, but it is not used as a substrate for methionine recycling. T. vaginalis also produces and exports high levels of S-methylcysteine, whereas only negligible levels were found in T. foetus which maintains significantly higher intracellular levels of cysteine. 13C-labeling confirmed that both cysteine and S-methylcysteine are synthesised by T. vaginalis; S-methylcysteine can be generated by recombinant T. vaginalis cysteine synthase using phosphoserine and methanethiol. T. foetus contained higher levels of ornithine and citrulline than T. vaginalis and exported increased levels of putrescine, suggesting greater flux through the arginine dihydrolase pathway. T. vaginalis produced and exported hydroxy acid derivatives of certain amino acids, particularly 2-hydroxyisocaproic acid derived from leucine, whereas negligible levels of these metabolites occurred in T. foetus. PMID: 29267346 [PubMed - in process]

Related Articles Major roles for minor bacterial lipids identified by mass spectrometry. Biochim Biophys Acta. 2017 11;1862(11):1319-1324 Authors: Garrett TA Abstract Mass spectrometry of lipids, especially those isolated from bacteria, has ballooned over the past two decades, affirming in the process the complexity of the lipidome. With this has come the identification of new and interesting lipid structures. Here is an overview of several novel lipids, from both Gram-negative and Gram-positive bacteria with roles in health and disease, whose structural identification was facilitated using mass spectrometry. This article is part of a Special Issue entitled: Bacterial Lipids edited by Russell E. Bishop. PMID: 27760388 [PubMed - in process]

Related Articles High-Throughput and High-Sensitivity Mass Spectrometry-Based N-Glycomics of Mammalian Cells. Methods Mol Biol. 2017;1503:185-196 Authors: Holst S, van Pelt GW, Mesker WE, Tollenaar RA, Belo AI, van Die I, Rombouts Y, Wuhrer M Abstract The current protocols for glycomic analysis of cells often require a large quantity of material (5-20 million cells). In order to analyze the N-glycosylation from small amounts of cells (≤1 million) as obtained from, for example, primary cell lines or cell sorting, and in a higher throughput approach, we set up a robust 96-well format PVDF-membrane based N-glycan release protocol followed by linkage-specific sialic acid stabilization, cleanup, and MALDI-TOF-MS analysis. We further evaluated the influence of PNGase F incubation time on the N-glycan profile. PMID: 27743367 [PubMed - in process]

Related Articles Site-Specific N- and O-Glycopeptide Analysis Using an Integrated C18-PGC-LC-ESI-QTOF-MS/MS Approach. Methods Mol Biol. 2017;1503:109-119 Authors: Stavenhagen K, Hinneburg H, Kolarich D, Wuhrer M Abstract The vast heterogeneity of protein glycosylation, even of a single glycoprotein with only one glycosylation site, can give rise to a set of macromolecules with different physicochemical properties. Thus, the use of orthogonal approaches for comprehensive characterization of glycoproteins is a key requirement. This chapter describes a universal workflow for site-specific N- and O-glycopeptide analysis. In a first step glycoproteins are treated with Pronase to generate glycopeptides containing small peptide sequences for enhanced glycosylation site assignment and characterization. These glycopeptides are then separated and detected using an integrated C18-porous graphitized carbon-liquid chromatography (PGC-LC) setup online coupled to a high-resolution electrospray ionization (ESI)-quadrupole time-of-flight (QTOF)-mass spectrometer operated in a combined higher- and lower-energy CID (stepping-energy CID) mode. The LC-setup allows retention of more hydrophobic glycopeptides on C18 followed by subsequent capturing of C18-unbound (glyco)peptides by a downstream placed PGC stationary phase. Glycopeptides eluted from both columns are then analyzed within a single analysis in a combined data acquisition mode. Stepping-energy CID results in B- and Y-ion fragments originating from the glycan moiety as well as b- and y-ions derived from the peptide part. This allows simultaneous site-specific identification of the glycan and peptide sequence of a glycoprotein. PMID: 27743362 [PubMed - in process]

Related Articles Sialic Acid Derivatization for the Rapid Subclass- and Sialic Acid Linkage-Specific MALDI-TOF-MS Analysis of IgG Fc-Glycopeptides. Methods Mol Biol. 2017;1503:49-62 Authors: de Haan N, Reiding KR, Wuhrer M Abstract Matrix-assisted laser desorption/ionization (MALDI)-time-of-flight (TOF)-mass spectrometry (MS) is a highly suitable method for the rapid analysis of IgG glycopeptides, providing a wealth of structural information. A limitation of this approach is that it generates a bias when analyzing sialylated species due to the labile nature of sialic acid glycosidic linkages. One way to overcome this problem is by chemical derivatization of the sialic acids. The method presented here results in both the stabilization of the sialic acids, as well as the differentiation of α2,3- and α2,6-linked sialic acids by mass. Described in this chapter are the isolation of IgG from plasma or serum, tryptic digestion of the samples, derivatization, and finally MALDI-TOF-MS measurement and data analysis. PMID: 27743358 [PubMed - in process]

Related Articles High-Throughput Analysis of IgG Fc Glycopeptides by LC-MS. Methods Mol Biol. 2017;1503:31-47 Authors: Falck D, Jansen BC, de Haan N, Wuhrer M Abstract This chapter contains a nanoscale liquid chromatography-mass spectrometry method for the glycoform profiling of the conserved Fc N-glycosylation site of monoclonal and polyclonal immunoglobulin G (IgG). It describes in detail LaCyTools, a program for automated data (pre-)processing of the obtained LC-MS data. The minimal sample preparation necessary is explained as well as an optional method for affinity purification of (polyclonal) antibodies from serum or plasma.After (optional) affinity purification, the pure IgG is cleaved with trypsin. The tryptic glycopeptides are separated almost exclusively on their peptide backbone. This ensures similar response factors for all glycoforms in the MS detection and allows the collection of separate glycoform profiles for different IgG isoforms or allotypes. LaCyTools automatically performs label-free (relative) quantitation of the obtained data after minimal manual input and additionally calculates several quality criteria which can be used for data curation at the level of both individual analytes and entire LC-MS runs. PMID: 27743357 [PubMed - in process]

Related Articles Development and application of a comprehensive lipidomic analysis to investigate Tripterygium wilfordii-induced liver injury. Anal Bioanal Chem. 2016 Jun;408(16):4341-55 Authors: Xie T, Zhou X, Wang S, Lu Y, Zhu H, Kang A, Deng H, Xu J, Shen C, Di L, Shan J Abstract Lipid metabolic pathways play pivotal roles in liver function, and disturbances of these pathways are associated with various diseases. Thus, comprehensive characterization and measurement of lipid metabolites are essential to deciphering the contributions of lipid network metabolism to diseases or its responses to drug intervention. Here, we report an integrated lipidomic analysis for the comprehensive detection of lipid metabolites. To facilitate the characterization of untargeted lipids through fragmentation analysis, nine formulas were proposed to identify the fatty acid composition of lipids from complex MS (n) spectrum information. By these formulas, the co-eluted isomeric compounds could be distinguished. In total, 250 lipids were detected and characterized, including diacylglycerols, triacylglycerols, glycerophosphoethanolamines, glycerophosphocholines, glycerophosphoserines, glycerophosphoglycerols, glycerophosphoinositols, cardiolipins, ceramides, and sphingomyelins. Integrated with the targeted lipidomics, a total of 27 inflammatory oxylipins were also measured. To evaluate the aberrant lipid metabolism involved in liver injury induced by Tripterygium wilfordii, lipid network metabolism was further investigated. Results indicated that energy lipid modification, membrane remodeling, potential signaling lipid alterations, and abnormal inflammation response were associated with injury. Because of the important roles of lipids in liver metabolism, this new method is expected to be useful in analyzing other lipid metabolism diseases. PMID: 27086014 [PubMed - in process]

Related Articles Editorial: Managing Strategies for Diverse Diseases: Challenges from Bench to Bedside Translation in Successful Drug Discovery and Development (Part B). Curr Pharm Des. 2016;22(20):2923-5 Authors: Kamal MA, Greig NH PMID: 27063488 [PubMed - in process]

Capillary electrophoresis-mass spectrometry for targeted and untargeted analysis of the sub-5 kDa urine metabolome of patients with prostate or bladder cancer: A feasibility study. J Chromatogr B Analyt Technol Biomed Life Sci. 2018 Jan 07;1074-1075:79-85 Authors: MacLennan MS, Kok MGM, Soliman L, So A, Hurtado-Coll A, Chen DDY Abstract Targeted and untargeted analyses of the sub-5 kDa urine metabolome of genitourinary cancer patients (prostate and/or bladder) were performed without chemical derivatization using capillary electrophoresis-electrospray ionization-mass spectrometry (CE-ESI-MS). For targeted analysis, endogenous levels of sarcosine and 5 other amino acid metabolites implicated in the progression of prostate cancer were quantified in four patients and in a pooled urine sample from healthy volunteers. An untargeted analysis (m/z 50 to 850) of patient urine was performed using the same CE-ESI-MS system identifying over 400 distinct molecular features per patient. All patient urine samples were collected at prostatectomy/cystectomy via catheter. Patient urine samples were filtered by centrifugation, with endogenous sarcosine enriched by solid-phase extraction, and the processed samples loaded onto CE-ESI-MS for analysis. Diagnostic information, digital pathological slides, and tissue samples were collected and stored in a comprehensive biobanking database. The introduction of urine sample collection into the surgery workflow was facile and is a promising strategy for addressing the translational research challenge of moving smoothly from "chromatogram to nomogram". PMID: 29334632 [PubMed - as supplied by publisher]

Comparative performance of different scale-down simulators of substrate gradients in Penicillium chrysogenum cultures: the need of a biological systems response analysis. Microb Biotechnol. 2018 Jan 15;: Authors: Wang G, Zhao J, Haringa C, Tang W, Xia J, Chu J, Zhuang Y, Zhang S, Deshmukh AT, van Gulik W, Heijnen JJ, Noorman HJ Abstract In a 54 m3 large-scale penicillin fermentor, the cells experience substrate gradient cycles at the timescales of global mixing time about 20-40 s. Here, we used an intermittent feeding regime (IFR) and a two-compartment reactor (TCR) to mimic these substrate gradients at laboratory-scale continuous cultures. The IFR was applied to simulate substrate dynamics experienced by the cells at full scale at timescales of tens of seconds to minutes (30 s, 3 min and 6 min), while the TCR was designed to simulate substrate gradients at an applied mean residence time (τc) of 6 min. A biological systems analysis of the response of an industrial high-yielding P. chrysogenum strain has been performed in these continuous cultures. Compared to an undisturbed continuous feeding regime in a single reactor, the penicillin productivity (qPenG ) was reduced in all scale-down simulators. The dynamic metabolomics data indicated that in the IFRs, the cells accumulated high levels of the central metabolites during the feast phase to actively cope with external substrate deprivation during the famine phase. In contrast, in the TCR system, the storage pool (e.g. mannitol and arabitol) constituted a large contribution of carbon supply in the non-feed compartment. Further, transcript analysis revealed that all scale-down simulators gave different expression levels of the glucose/hexose transporter genes and the penicillin gene clusters. The results showed that qPenG did not correlate well with exposure to the substrate regimes (excess, limitation and starvation), but there was a clear inverse relation between qPenG and the intracellular glucose level. PMID: 29333753 [PubMed - as supplied by publisher]

Report of an Italian family carrying a typical Indian variant of the Nilgiris tribal groups resulting from a de novo occurrence. Hum Genome Var. 2018;5:17057 Authors: Canu G, Mazzuccato G, Urbani A, Minucci A Abstract G6PD deficiency is quite common in Italy where it is characterized by extreme molecular and biochemical heterogeneity. We report a 15-year-old Italian boy with G6PD Nilgiri (c.593G>A, p.Arg198His), a typical Indian variant of the Nilgiris tribal groups. Further, this variant was biochemically characterized, and the molecular screening of the family highlighted a de novo mutational event. To date, this family is the first Caucasian family carrying the G6PD Nilgiri variant. PMID: 29333274 [PubMed]

Novel Filtration Markers for GFR Estimation. EJIFCC. 2017 Dec;28(4):277-288 Authors: Karger AB, Inker LA, Coresh J, Levey AS, Eckfeldt JH Abstract Creatinine-based glomerular filtration rate estimation (eGFRcr) has been improved and refined since the 1970s through both the Modification of Diet in Renal Disease (MDRD) Study equation in 1999 and the CKD Epidemiology Collaboration (CKD-EPI) equation in 2009, with current clinical practice dependent primarily on eGFR for accurate assessment of GFR. However, researchers and clinicians have recognized limitations of relying on creatinine as the only filtration marker, which can lead to inaccurate GFR estimates in certain populations due to the influence of non-GFR determinants of serum or plasma creatinine. Therefore, recent literature has proposed incorporation of multiple serum or plasma filtration markers into GFR estimation to improve precision and accuracy and decrease the impact of non-GFR determinants for any individual biomarker. To this end, the CKD-EPI combined creatinine-cystatin C equation (eGFRcr-cys) was developed in 2012 and demonstrated superior accuracy to equations relying on creatinine or cystatin C alone (eGFRcr or eGFRcys). Now, the focus has broadened to include additional novel filtration markers to further refine and improve GFR estimation. Beta-2-microglobulin (B2M) and beta-trace-protein (BTP) are two filtration markers with established assays that have been proposed as candidates for improving both GFR estimation and risk prediction. GFR estimating equations based on B2M and BTP have been developed and validated, with the CKD-EPI combined BTP-B2M equation (eGFRBTP-B2M) demonstrating similar performance to eGFR and eGFR. Additionally, several studies have demonstrated that both B2M and BTP are associated with outcomes in CKD patients, including cardiovascular events, ESRD and mortality. This review will primarily focus on these two biomarkers, and will highlight efforts to identify additional candidate biomarkers through metabolomics-based approaches. PMID: 29333147 [PubMed]

Highlight report: Metabolomics in hepatotoxicity testing. EXCLI J. 2017;16:1323-1325 Authors: Ghallab A PMID: 29333135 [PubMed]

A robust and extendable sheath flow interface with minimal dead volume for coupling CE with ESI-MS. Talanta. 2018 Apr 01;180:376-382 Authors: Fang P, Pan JZ, Fang Q Abstract In this paper, we describe a robust sheath flow-based CE-MS interface with minimal interface dead volume based on an extended pattern. A 20µm i.d. × 90µm o.d. fused-silica capillary with a chemically-etched thin-wall tip (30µm o.d.) was used as the separation capillary as well as electrospray emitter, and a 200µm i.d. × 375µm o.d. capillary with a tapered tip (40µm o.d.) was used as the sheath flow capillary. An extendable sheath-flow interface mode was adopted by decreasing the thickness of separation capillary tip and extending the separation capillary tip out from the sheath flow capillary tip, and allowing the sheath flow to be transferred to the separation capillary tip along its outer surface, forming a surface sheath flow to mix with sample flow at the separation capillary tip. Such a strategy could significantly reduce the interface dead volume and thus improve the CE separation efficiency and detection sensitivity, as well as evidently enhance the working reliability of the CE-MS interface. We investigated various factors affecting the interface performance, including capillary extending distance, emitter diameters, sheath flow capillary shape, and sheath flow rate. Under the optimized conditions, a minimal interface dead volume of ca. 4pL was obtained which is the smallest one compared with previously-reported sheath flow-based CE-MS interfaces. The feasibility and applicability of the present CE-MS interface were demonstrated in the separation of a peptide mixture with high separation efficiency of 2.07-3.38µm plate heights and good repeatabilities (< 6.1% RSD, n = 5). We except such a simple and robust interface could provide a possible solution for the development of commercial CE-MS interfaces differing from the currently-used ones, and has the potentials to be applied in routine analytical laboratories for various studies such as proteomics, metabolomics, or single cell analysis. PMID: 29332826 [PubMed - in process]

Salivary metabolomics profile of patients with recurrent aphthous ulcer as revealed by liquid chromatography-tandem mass spectrometry. J Int Med Res. 2018 Jan 01;:300060517745388 Authors: Li Y, Wang D, Zeng C, Liu Y, Huang G, Mei Z Abstract Objective We compared the salivary nontargeted metabolite profiles between patients with recurrent aphthous ulcer (RAU) and healthy individuals to investigate the metabolic alterations associated with RAU. Methods Saliva samples were collected from 45 patients with RAU and 49 healthy individuals, and the salivary metabolites were quantified using liquid chromatography-tandem mass spectrometry. The metabolomic profiles were then analyzed using multivariate and univariate statistical methods, and enrichment of the metabolites in various biological pathways was assessed. Results In total, 206 significant differentiating metabolites (Wilcoxon test, false discovery rate [FDR] of <0.05) were identified between patients with RAU and healthy individuals. These metabolites were implicated in tryptophan metabolism, steroid hormone biosynthesis, and other metabolic pathways. Two commonly circulating steroids, estrone sulfate and dehydroepiandrosterone sulfate, were significantly lower in the saliva of patients with RAU (Wilcoxon test, FDR < 0.05, power > 0.9). Principal component analysis and partial least-squares discriminant analysis revealed metabolic perturbations involving RAU, and receiver operating characteristic curve analysis with several metabolites showed good diagnostic ability for RAU. Conclusions The results of this study indicate that patients with RAU are characterized by metabolic imbalances. Psychogenic factors, endocrinopathies, and immunosuppression may contribute to the onset of RAU. PMID: 29332424 [PubMed - as supplied by publisher]

Related Articles Highly Time-Resolved Metabolic Reprogramming toward Differential Levels of Phosphate in Chlamydomonas reinhardtii. J Microbiol Biotechnol. 2017 Jun 28;27(6):1150-1156 Authors: Jang CH, Lee G, Park YC, Kim KH, Lee DY Abstract Understanding phosphorus metabolism in photosynthetic organisms is important as it is closely associated with enhanced crop productivity and pollution management for natural ecosystems (e.g., algal blooming). Accordingly, we exploited highly time-resolved metabolic responses to different levels of phosphate deprivation in Chlamydomonas reinhardtii, a photosynthetic model organism. We conducted non-targeted primary metabolite profiling using gas-chromatography time-of-flight mass spectrometric analysis. Primarily, we systematically identified main contributors to degree-wise responses corresponding to the levels of phosphate deprivation. Additionally, we systematically characterized the metabolite sets specific to different phosphate conditions and their interactions with culture time. Among them were various types of fatty acids that were most dynamically modulated by the phosphate availability and culture time in addition to phosphorylated compounds. PMID: 28372038 [PubMed - indexed for MEDLINE]

Related Articles Molecular Identification, Enzyme Assay, and Metabolic Profiling of Trichoderma spp. J Microbiol Biotechnol. 2017 Jun 28;27(6):1157-1162 Authors: Bae SJ, Park YH, Bae HJ, Jeon J, Bae H Abstract The goal of this study was to identify and characterize selected Trichoderma isolates by metabolic profiling and enzyme assay for evaluation of their potential as biocontrol agents against plant pathogens. Trichoderma isolates were obtained from the Rural Development Administration Genebank Information Center (Wanju, Republic of Korea). Eleven Trichoderma isolates were re-identified using ribosomal DNA internal transcribed spacer (ITS) regions. ITS sequence results showed new identification of Trichoderma isolates. In addition, metabolic profiling of the ethyl acetate extracts of the liquid cultures of five Trichoderma isolates that showed the best anti-Phytophthora activities was conducted using gas chromatography-mass spectrometry. Metabolic profiling revealed that Trichoderma isolates shared common metabolites with well-known antifungal activities. Enzyme assays indicated strong cell walldegrading enzyme activities of Trichoderma isolates. Overall, our results indicated that the selected Trichoderma isolates have great potential for use as biocontrol agents against plant pathogens. PMID: 28372034 [PubMed - indexed for MEDLINE]

Related Articles Transcriptomic and metabolic analyses provide new insights into chilling injury in peach fruit. Plant Cell Environ. 2017 Aug;40(8):1531-1551 Authors: Wang K, Yin XR, Zhang B, Grierson D, Xu CJ, Chen KS Abstract Low temperature conditioning (LTC) alleviates peach fruit chilling injury but the underlying molecular basis is poorly understood. Here, changes in transcriptome, ethylene production, flesh softening, internal browning and membrane lipids were compared in fruit maintained in constant 0 °C and LTC (pre-storage at 8 °C for 5 d before storage at 0 °C). Low temperature conditioning resulted in a higher rate of ethylene production and a more rapid flesh softening as a result of higher expression of ethylene biosynthetic genes and a series of cell wall hydrolases. Reduced internal browning of fruit was observed in LTC, with lower transcript levels of polyphenol oxidase and peroxidase, but higher lipoxygenase. Low temperature conditioning fruit also showed enhanced fatty acid content, increased desaturation, higher levels of phospholipids and a preferential biosynthesis of glucosylceramide. Genes encoding cell wall hydrolases and lipid metabolism enzymes were coexpressed with differentially expressed ethylene response factors (ERFs) and contained ERF binding elements in their promoters. In conclusion, LTC is a special case of cold acclimation which increases ethylene production and, operating through ERFs, promotes both softening and changes in lipid composition and desaturation, which may modulate membrane stability, reducing browning and contributing to alleviation of peach fruit chilling injury. PMID: 28337785 [PubMed - indexed for MEDLINE]